Continuous Infusion of Recombinant Activated Factor VII Safe, Effective in Management of Congenital Hemophilia

The efficacy of recombinant activated factor VII administered by continuous infusion (rFVIIa CI) in patients with congenital hemophilia with inhibitors (CHwI) or congenital factor VII deficiency (C7D) undergoing surgery and during bleeding episodes appears to be high and comparable to that of rFVIIa delivered by bolus injection (rFVIIa BI), according to a recent literature review published in the Journal of Blood Medicine.¹ The study authors found that reported adverse drug reactions (ADRs) with rFVIIa CI were consistent with the established safety profile of rFVIIa BI.

Although rFVIIa is approved by the FDA for BI administration only for the treatment of bleeding episodes and the prevention of bleeding in surgical interventions or invasive procedures in patients with hemophilia A or B with inhibitors, congenital C7D, and Glanzmann’s thrombasthenia with refractoriness to platelets with or without antibodies, the current World Federation of Hemophilia guidelines state that the use of CI may reduce the amount of clotting factor concentrates administered, and thereby may be cost-effective, particularly in patients with severe hemophilia.² (rFVIIa is also indicated for the treatment of bleeding episodes and the prevention of bleeding in surgical interventions or invasive procedures in adults with acquired hemophilia).

The objective of the current literature review was to document the clinical experience of patients with CHwI and C7D who were treated with rFVIIa CI in order to evaluate its safety and efficacy in these patient populations. The review identified patients treated with rFVIIa CI between January 1, 1995, and September 30, 2016. The studies had to be published in English and had to include data from patients with CHwI or C7D even if other indicated uses of rFVIIa were also presented. The literature search captured a total of 241 patients who experienced 453 bleeding episodes, 223 surgical procedures, and 46 unspecified episodes (bleeds/surgeries) in which rFVIIa CI was used as part of the treatment regimen. The following were used in the data analysis:

• The safety and efficacy of 50 mcg/kg/h CI of rFVIIa following a 90 mcg/kg BI, versus a standard bolus injection regimen, was reported for 24 patients with CHwI undergoing elective surgery in an open label, randomized, phase 3 trial. Efficacy was similar between CI and BI groups at all postoperative time points assessed.
• A postmarketing surveillance study reported effective (80%) and partially effective (20%) CI of rFVIIa in a Japanese cohort of 10 patients with CHwI who underwent 15 surgical procedures.
• The safety and dosing of rFVIIa CI in patients with CHwI (n = 193) and C7D (n = 26), were reported in 11 prospective studies, 10 retrospective studies, and 30 case reports, with no unexpected safety findings reported.

The study authors said that rFVIIa has been performed safely and effectively in patients with CHwI and C7D undergoing surgery and during bleeding episodes in patients with CHwI. “CI may be a useful alternative to BI for the perioperative management of bleeding in some patients with CHwI or C7D,” they conclude. They note that the study’s analysis was limited by the inconsistent use of concomitant hemostatic agents and highly variable dosing of rFVIIa for BIs and CIs across patients and reports, which complicates the interpretation of safety and efficacy assessments. However, they point out that this and other limitations are common in the context of rare diseases, and their analysis benefited from systematically searching the published literature to obtain the maximum amount of patient data relevant to rFVIIa CI in populations of interest.

The authors recommend performing a direct comparison between BI and CI of rFVIIa in patients with C7D, the absence of which complicates the ability to recommend therapeutic dose guidelines for CI administration in this patient population.

References

1. Rajpurkar M, Cooper DL. Continuous infusion of recombinant activated factor VII: a review of data in congenital hemophilia with inhibitors and congenital factor VII deficiency. J Blood Med. 2018;9:227-239.
2. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):e1-e47.